[Federal Register: October 27, 1994]
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Part II
Department of Health and Human Services
_______________________________________________________________________
Food and Drug Administration
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21 CFR Part 600
Adverse Experience Reporting Requirements For Licensed Biological
Products; Final Rule
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 600
[Docket No. 85N-0506]
RIN 0905-AB53
Adverse Experience Reporting Requirements for Licensed Biological
Products
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule.
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SUMMARY: The Food and Drug Administration (FDA) is amending the
regulations to require manufacturers of licensed biological products
(hereinafter referred to as licensed manufacturers) to report to FDA
within 15 working days all adverse experiences associated with the use
of a biological product that are both serious and unexpected; any
significant increase in the frequency of a serious, but expected
adverse experience; periodically, all other adverse experiences; and
product distribution and disposition data. FDA is taking this action to
provide a mechanism under which licensed manufacturers would inform the
agency, on a timely basis, of any unanticipated safety problems with
marketed biological products.
EFFECTIVE DATE: This regulation is effective December 27, 1994.
ADDRESSES: Copies of Form FDA-3500A may be obtained from the Center for
Biologics Evaluation and Research (HFM-210), Food and Drug
Administration, 1401 Rockville Pike, suite 200N, Rockville, MD 20852-
1448. Additional copies of the form may be obtained from the
Consolidated Forms and Publications Distribution Center, 3222 Hubbard
Rd., Landover, MD 20785. Copies of the VAERS form may be obtained from
the Vaccine Adverse Event Reporting System (VAERS) by calling 1-800-
822-7967.
All reports required by this regulation pertaining to nonvaccine
biological products should be sent to the Center for Biologics
Evaluation and Research (address above). All reports required by this
regulation pertaining to vaccines should be sent to VAERS, P.O. Box
1100, Rockville, MD 20849-1100.
FOR FURTHER INFORMATION CONTACT: Paula S. McKeever, Center for
Biologics Evaluation and Research (HFM-635), Food and Drug
Administration, 1401 Rockville Pike, Rockville, MD 20852-1448, 301-594-
3074.
SUPPLEMENTARY INFORMATION:
I. Introduction
In the Federal Register of April 24, 1979 (44 FR 24233), FDA made
available for public comment a draft proposed regulation that would
require the maintenance of records and submission of reports of adverse
experiences involving licensed biological products. After evaluating
the comments received and analyzing other information, FDA issued a
proposed regulation (hereinafter referred to as the 1990 proposal) and
notice of availability of a draft guideline in the Federal Register of
March 29, 1990 (55 FR 11611 and 11655, respectively). The 1990 proposal
was to require all manufacturers of licensed biological products to
submit the following reports to FDA: (1) Alert reports within 15
working days of receipt of adverse experiences associated with the use
of a licensed biological product that are both ``serious and
unexpected,'' and of any ``significant increase in frequency'' of an
adverse experience that is both ``serious and unexpected;'' and (2)
periodic reports of all adverse experiences, including both serious and
nonserious adverse experiences, that are not included in a 15-day Alert
report. The statutory authority for promulgating these regulations was
described in detail in the preamble to the 1990 proposal (55 FR 11611
at 11613). The agency provided 60 days for interested persons to submit
written comments on the 1990 proposal.
Prior to promulgation of this final rule, only adverse experiences
associated with certain childhood vaccines (see 53 FR 10565, April 1,
1988) and fatalities resulting from blood collection or transfusion
(Sec. 606.170 (21 CFR 606.170)) were required to be reported to FDA for
biological products. Although many manufacturers of other types of
biological products voluntarily submit adverse experience reports to
FDA, there has not necessarily been consistent or complete reporting
from all licensed manufacturers.
In the Federal Register of June 3, 1993 (58 FR 31596), FDA issued a
notice announcing the availability of a new form for reporting adverse
events and product problems with human drug products, biologic
products, medical devices, special nutritional products, and other
products regulated by FDA. One version of the form (FDA Form 3500) was
made available for use by health professionals for voluntary reporting;
the other version of the form (FDA Form 3500A) was made available for
use by user facilities, distributors, and manufacturers for reporting
that is required by statute or by FDA regulation. The new form is part
of an FDA MEDWATCH program which is intended to consolidate and
simplify reporting of adverse events and product problems for all FDA-
regulated products.
Many of the comments received in response to the 1990 proposal,
while having merit, if implemented would require changes to the
regulations governing the reporting of adverse experiences for biologic
products which would cause these requirements to diverge significantly
from the requirements and reporting program for drugs as provided in
Secs. 310.305 and 314.80 (21 CFR 310.305 and 314.80)). Such a
divergence would be contrary to the MEDWATCH program which is intended,
in part, to enhance consistency in the reporting and collection of
information on adverse experiences related to FDA-regulated products.
Rather than making such significant changes in this final rule, FDA is
issuing a notice of proposed rulemaking elsewhere in this issue of the
Federal Register which would appropriately amend the requirements in
Secs. 310.305, 312.32 (21 CFR 312.32), and 314.80 for reporting of
adverse experiences related to human drugs and the requirements in this
final rule (Secs. 600.80 and 600.81) for reporting adverse experiences
related to biological products. Later in this preamble, in response to
a number of public comments which request significant changes to the
regulations, FDA refers to the proposed rule which provides a more
substantial discussion of the issues involved.
Elsewhere in this issue of the Federal Register, FDA is also
announcing the availability of a guideline entitled ``The Guideline for
Adverse Experience Reporting for Licensed Biological Products''
(referred to as ``guideline'' in this final rule). The guideline
discusses in detail the reports required by this rule, and provides
guidance concerning some appropriate means of meeting the reporting
requirements.
II. Highlights of the Final Rule
This final rule establishes procedures under Secs. 600.80 and
600.81 for licensed manufacturers to inform FDA about adverse
experiences that are associated with the use of a licensed biological
product and about biological product distribution. These procedures are
intended to support the agency's efforts to protect the public safety
by providing the agency with the information necessary for effective
postmarket surveillance of biological products. This final rule
requires licensed manufacturers of biological products to submit
various reports to the agency and specifies the timeframes for
submission of these reports. The reports are: (1) Fifteen-day Alert
reports, (2) increased frequency alert reports, (3) periodic adverse
experience reports and (4) distribution reports. The timeframes and
contents of these adverse experience reports were the subject of
numerous comments, which are discussed below. In addition to the
reporting requirements, the final rule specifies record-keeping
requirements, provides for exemptions of two categories of biological
products, provides a disclaimer regarding causality, and provides for
license revocation if licensed manufacturers fail to establish and
maintain records and submit the required reports. In addition, this
final rule provides procedures, under Sec. 600.90, for applying for
waivers from any of the reporting requirements.
The requirements in this final rule are consistent with existing
requirements in Secs. 314.80 and 314.81 (21 CFR 314.81) regarding
approved new drug products, except when differences are necessary to
accommodate laws, terminology, procedures, and characteristics unique
for biological products.
A. Scope
The new procedures apply to all licensed manufacturers of
biological products and any person, other than the licensed
manufacturer of a biological product, whose name appears on the label
of a licensed biological product as a manufacturer, packer,
distributor, shared manufacturer, joint manufacturer, or a participant
in divided manufacturing.
B. Format
The format of Sec. 600.80 has been revised from what was proposed
to be consistent with Sec. 314.80. FDA believes that the revised format
will reduce the burden for manufacturers following the regulations for
both drug and biological products.
III. Comments on the Proposed Rule and FDA Responses
FDA received 15 letters of comment on the proposed rule. Most
letters contained numerous comments on various areas of the proposed
rule. Four of these comments supported codification of the reporting
requirements for adverse experiences associated with biological
products. Other comments either addressed particular paragraphs in the
proposed regulation or dealt with the effect of the regulation on a
particular type of biological product. In addition to the amendments
discussed below, editorial changes were made throughout the rule. A
summary of these comments and the agency's responses follow:
A. General Comments
1. Consistency With Section 314.80
Two comments on Sec. 600.80 recognized the reporting issues unique
to biological products and were supportive of both the 1990 proposal
and the draft guideline for recognizing the differences between drugs
and biological products. In contrast, four comments requested that FDA
not deviate from the rules and guidelines applicable to drugs and
requested that the regulations for reporting adverse experiences for
biological products mirror the regulations for drugs.
FDA intends these rules to be consistent with other agency
initiatives and requirements regarding adverse experience reporting for
drugs and medical devices wherever practical. This is demonstrated by
the new adverse experience reporting Form FDA-3500A, which, with the
exception of adverse experience reports associated with vaccines, is to
be used for reporting of adverse events associated with drugs,
biologics, and certain other products regulated by FDA. The final rule
contains requirements unique to biological products only when necessary
to accommodate the laws applicable only to biological products, such as
vaccines, or to accommodate special characteristics of biological
products.
2. Agency Review of Adverse Experience Reports
One comment requested that the unit of FDA responsible for
receiving adverse experience reports for drugs continue to be
responsible for the adverse experiences for biologics to assure
consistency of interpretation of the regulations and dissemination of
information within FDA.
The agency intends to maintain consistency between the Center for
Biologics Evaluation and Research (CBER) and the Center for Drugs
Evaluation and Research (CDER) in the interpretation of the
regulations, especially with respect to terminology. A separate unit
was created with the responsibilities related to postmarketing
surveillance of licensed biological products because the agency
recognizes that these products can present different safety concerns
due to inherent differences in the products. In addition, the National
Childhood Vaccine Injury Act of 1986 (NCVIA) mandated specific
reporting requirements for manufacturers of certain vaccines and for
health care providers administering those vaccines. VAERS was
established to receive these required reports, as well as reports on
other vaccines. The VAERS program is administered jointly by FDA and by
the Centers for Disease Control and Prevention (CDC) and replaces
previous vaccine reporting systems within both agencies. Section
600.80(c) has been amended in the final rule to reflect the change of
address for submitting reports due to the reorganization and relocation
of CBER.
3. Clarification of Overlap Between the Vaccine Adverse Event Reporting
System and Sec. 600.80
Comments were received requesting clarification of overlap between
the requirements of NCVIA and the regulations.
NCVIA created a new Title XXI of the Public Health Service Act
(the PHS Act). Section 2125 of the PHS Act (42 U.S.C. 300aa-25)
requires health care providers who administer certain vaccines and
manufacturers of the vaccines to report specified adverse experiences,
occurring within specified time intervals after administration of the
vaccines. These adverse experience reports are submitted to VAERS,
which is jointly managed by FDA and CDC and became operational on
November 1, 1990. A form VAERS-1 was developed for these reports. When
the requirements set forth in both Sec. 600.80 and NCVIA necessitate
reporting of an adverse event, licensed manufacturers of vaccines are
not required to submit duplicate reports to VAERS and FDA. Submission
of the report to VAERS is sufficient. However, licensed manufacturers
of vaccines must comply with the regulations in Sec. 600.80. Therefore,
any requirements in these regulations that are in addition to those
specified in the NCVIA must be satisfied. For example, although NCVIA
does not specify the time periods for submission of adverse experience
reports, the time periods set forth in Sec. 600.80 apply to reports
being submitted to VAERS.
4. Requests for Waivers
Six comments requested waivers from the reporting requirements for
specific types of adverse experiences or for certain categories of
biological products. These requests for waivers were with respect to
parts or all of the requirements of proposed Sec. 600.80. In addition,
one comment requested that the final rule specify the provisions for
requesting a waiver.
The agency agrees that the provisions for a waiver should be
specified in the final rule and has added a new Sec. 600.90 describing
the procedures for requesting a waiver. Section 600.90 is similar to
Sec. 314.90 (21 CFR 314.90), the provision for waivers for drugs or
antibiotics. Manufacturers and other interested persons should submit
requests for waivers as provided in Sec. 600.90 of the final rule.
5. Economic Assessment
One comment requested clarification of FDA's estimate of the cost
of complying with the reporting requirements of the proposed rule of
approximately $255,490. The company estimates that its cost in labor
and overhead would be approximately $40,000. In contrast, another
comment stated that the company did not anticipate that this reporting
requirement would significantly alter the manner in which companies
would share their postmarketing information with FDA.
The agency's assessment of cost was made over 4 years ago when both
the number of approved biological products was fewer and costs somewhat
less. In addition, the agency's figures did not take into account
overhead and other costs associated with basic manufacturing practices.
Every responsible manufacturer and distributor, regardless of the type
of product manufactured, implements a means to receive inquiries about
the quality and adverse effects of its products as good manufacturing
practices and as an accepted part of doing business. Therefore, this
cost has not been included in assessing the cost of this regulation.
The costs assessed for this regulation only related to the specific
costs incurred by the requirements in the regulation which are in
addition to customary business practice. The costs of the regulation
are for preparation of the specific reports and analyses required by
the regulation and do not include the normal operating and overhead
costs of doing business. The revised economic assessment is discussed
at the end of this preamble.
B. Definitions Section 600.80(a)
1. Adverse Experience
Four comments requested clarification of the definition of
``adverse experience'' in proposed Sec. 600.80(a), particularly the
phrase ``significant failure of expected pharmacological action * * *
whether or not considered product related.'' One comment stated that
the word ``significant'' has one meaning in the definition of ``adverse
experience'' and another statistical meaning in the usage of the term
``increased frequency'' in proposed Sec. 600.80(c)(1)(ii) and requested
that the word be used consistently with the same meaning throughout the
regulation. Another comment requested a definition of ``significant
failure'' as used in the definition of adverse experience. One comment
requested that the definition be amended to require reporting of
changes in failure rates instead of any significant failure. One
comment gave the following examples of incidents that would be
considered an adverse experience with any significant failure: a
patient who dies of acute myocardial infarction in spite of
thrombolytic therapy; or a patient who dies of congestive heart failure
despite diuretic therapy, i.e., deaths from progression of the
indicated disease. One comment stated that it concurs with the agency's
definition of ``adverse experience'' because it does not include ``loss
of response'' as an adverse experience. The comment goes on to state
that loss of immunity over time from a vaccine is not logically an
adverse event.
The agency agrees that the word ``significant'' when used in this
context is a source of confusion and ambiguity. To eliminate this
source of confusion and to encourage the reporting of all adverse
experiences, FDA revised Sec. 314.80 to delete the word ``significant''
from the definition of ``adverse experience'' in the reporting
requirements for drugs (see 57 FR 17950, April 28, 1992) and is
revising the definition of ``adverse experience'' in this final rule by
deleting the word ``significant.''
The agency is retaining the proposed language in the definition of
``adverse experience'' instead of adopting the suggestion to require
reporting only of changes in failure rate because a ``change in failure
rate'' can only be determined retrospectively. A change in failure rate
is to be reported in an increased frequency report; however, a failure
of expected pharmacological action that causes a serious and unexpected
adverse experience in humans should be reported within 15 days
regardless of the rate of such reports.
The agency believes that the examples given may or may not indicate
a ``failure of expected pharmacological action.'' For example, patients
with congestive heart failure often have irreparable kidney damage
which even the most potent diuretics cannot overcome. In such a
situation congestive heart failure would not be a failure of expected
pharmacologic action. However, the extent of pre-existing kidney damage
and the degree to which kidney failure may be expected would be
demonstrable through kidney function tests prior to medication.
Therefore, FDA is not amending the definition of adverse experience as
requested.
The agency agrees partially with the comment regarding ``loss of
response.'' If loss of immunity over time is the expected pharmacologic
action of the vaccine, then it is not an adverse experience. If loss of
immunity is due to a patient's compromised immune system, this also
would not be considered an adverse experience. However, loss of
immunity due to an unexpected failure of the pharmacologic action of
the vaccine, thereby leaving recipients susceptible to a communicable
disease, is an adverse experience and should be reported. The guideline
points out that for purposes of adverse events reporting, ``lack of
effect'' is generally synonymous with ``failure to produce the expected
pharmacologic action.'' Certain products are indicated for immunization
through a recommended course of several doses to achieve a specified
level of antibody titer to provide seroprotection. In this case, ``lack
of effect'' is synonymous with ``failure to produce the expected
pharmacologic action'' only when adequate seroconversion is not
achieved following the final dose.
2. Blood Components
One comment noted that the language in the proposed
Sec. 600.80(l)(1) and preamble refers to blood components yet the
section of the CFR upon which the exemption is predicated
(Sec. 606.170) refers to blood products. The comment specifically asked
whether albumin and immunoglobulin are exempt from the rule and
requested clarification of the meaning of blood component in
Sec. 600.80(a).
FDA is clarifying the regulations by adding in Sec. 600.80(a) of
the final rule a reference to 21 CFR 606.3(c), which defines a ``Blood
Component'' as ``that part of a single-donor unit of blood separated by
physical or mechanical means.'' The exemption in Sec. 600.80(l), for
reporting adverse experiences associated with blood components, does
not include products derived from pooled blood such as albumin or
immunoglobulin. Therefore, albumin and immunoglobulin are biological
products subject to this rule.
In a future issue of the Federal Register FDA intends to propose
revisions to Sec. 606.170, concerning reports related to blood
collection or transfusion.
3. Disability
Two comments requested that a definition for ``disability'' be
included in Sec. 600.80(a) as the phrase ``permanently disabling'' is
used in the definition of ``serious.''
The agency agrees that the term ``disability'' should be defined
and is proposing a definition in the notice of proposed rulemaking
found elsewhere in this issue of the Federal Register.
4. Increased Frequency
Four comments on proposed Sec. 600.80(a) requested clarification of
the definition for ``increased frequency.'' Two comments stated that
the proposed definition of ``increased frequency,'' as an increase in
the rate of occurrence, is misleading inasmuch as the rate of
occurrence cannot be determined by a spontaneous reporting system. Two
comments requested that the definition of increased frequency take into
account an adjustment for product exposure.
The agency agrees with these comments and is revising the
definition in Sec. 600.80(a) as follows: ``Increased frequency means an
increase in the rate of occurrence of a particular adverse biological
product experience, after appropriate adjustment for exposure to the
biological product.''
5. Life Threatening
One comment requested that a definition for ``life threatening'' be
included, similar to that found in 21 CFR 312.32.
The agency agrees and is proposing a definition of ``life
threatening'' in the notice of proposed rulemaking found elsewhere in
this issue of the Federal Register.
6. Serious
Three comments noted discrepancies between the preamble,
Sec. 600.80(a) of the proposed rule, reporting form FDA-1639, and the
draft guideline regarding the meaning of the term ``serious.'' The
discrepancies consisted of differences in scope regarding the
reportability of overdose, prolonged hospitalization, and severe
disability.
To clarify the discrepancies concerning ``overdose,'' the agency
reevaluated the definition of ``serious'' to determine whether all
overdoses should be included in the definition and determined that not
all overdoses are serious.
In resolving the discrepancies in the definition of ``serious''
regarding inpatient hospitalization, the agency determined that
prolonged inpatient hospitalization should be included as a serious
adverse event. FDA is proposing a revision of the definition of
``serious'' to exclude the term ``overdose'' and to include ``requires
or prolongs inpatient hospitalization'' in the notice of proposed
rulemaking found elsewhere in this issue of the Federal Register.
The term ``disability'' is discussed in section III.B.3 of this
preamble.
7. Significant
One comment requested that a definition for the word
``significant'' which compensates for changes in use patterns be
included in Sec. 600.80(a). The comment is in reference to the use of
the term ``significant'' in the increased frequency alert reports.
The agency agrees in part with this comment. The agency considers
``significant'' in this context to mean a noticeable or measurable
increase in frequency after adjustment for documented changes in use
patterns. However, the agency is not codifying this definition in
Sec. 600.80(a) because ``significant'' may have a different meaning in
a different context within adverse experience reporting. The guideline
provides clarifying examples utilizing a formula and table to determine
if there is a significant increase in frequency of an adverse
experience.
8. Clarification Between Product Defects and Adverse Experiences
One comment requested clarification regarding the definitions in
Sec. 600.80(a) for adverse experiences and the reporting of product
defects.
The definition of ``adverse experience'' in Sec. 600.80(a)
specifies that the adverse experience must be ``associated with the use
of a biological product in humans * * *.'' Therefore, product defects
either discovered in the manufacturing process or not associated with
an adverse experience in humans are not subject to this regulation.
These defects may be reportable under good manufacturing practice
regulations covered in 21 CFR 600.14. However, product defects which
result in an adverse experience in a human are subject to reporting
under Sec. 600.80.
C. Review of Adverse Experiences Section 600.8(b)
1. Reported by Scientific Papers or Competitors
One comment on proposed Sec. 600.80(b) stated that to place
responsibility on the licensed manufacturer for review of all adverse
experience information pertaining to its product from any source,
including published and unpublished scientific papers, is both time
consuming and possibly open to abuse by competitors. The comment went
on to state that if an unsubstantiated mailing from a competitor
alleged ``adverse or unexpected experiences,'' the licensed
manufacturer becomes subject to the entire 15-day alert procedures,
including the need to conduct, if not actually report to FDA, the
followup investigation. One comment asked the agency to specify the
degree of vigor that licensed manufacturers should use to pursue
reports of adverse experiences in the scientific literature.
Section 600.80(b) is not intended to require licensed manufacturers
to discover every published and unpublished report on its product.
However, once a report of an adverse experience is made known to the
licensed manufacturer, it is the licensed manufacturer's responsibility
to comply with the requirements in Sec. 600.80 regardless of the source
of the adverse experience report. It is acceptable for the licensed
manufacturer to come to the conclusion that the mailing or publication
alleging an adverse experience is false or misleading and report this
conclusion to the agency. In some cases the agency may take appropriate
regulatory action against persons preparing a false or misleading
report of an adverse experience.
2. Lack of Response Reports
One comment on proposed Sec. 600.80(b) stated that ``lack of
response'' complaints from consumers do not have sufficient validity to
aid in decisionmaking and therefore should not be submitted to FDA.
Another comment requested that ``lack of response'' should not be
submitted for single patient incidents but limited to studies.
The agency believes that all reports of ``lack of response'' for
single patient incidents should be reviewed and submitted by the
licensed manufacturer. Complaints from consumers should be verified
with the patient's health-care provider, if possible, prior to being
submitted to FDA.
D. Clarification of Reporting Requirements Section 600.80(c)
1. Terminology
Two comments on proposed Sec. 600.80(c) requested clarification of
terminology between the term ``applicant'' used in Sec. 314.80 and the
term ``manufacturer'' used in proposed Sec. 600.80. One comment
preferred the term ``licensee'' for this regulation regarding
biological products.
The agency uses the term ``licensed manufacturer'' in these rules
because it presents a more accurate representation of those required to
comply with these regulations. These rules are being promulgated for
the purpose of gathering postmarketing surveillance information, which
will occur after product licensing.
2. Responsibilities
Two comments requested clarification of responsibilities for joint
manufacturers, shared manufacturers, divided manufacturers, and
contractual manufacturers so that duplicate adverse experience reports
are not submitted. One comment requested that, in order to avoid
duplicate reporting or failures to report adverse experiences, the
agency should add language similar to Sec. 314.80(c)(1)(iii). Another
comment requested that the agency specify the reporting requirements of
a nonapplicant.
FDA recognizes that manufacturing of a biological product can be
shared or divided among a number of business establishments. In the
Federal Register of November 25, 1992 (57 FR 55544), FDA published a
notice that discussed cooperative manufacturing arrangements for
licensed biological products. In addition, 21 CFR 600.12(e) requires
that ``each participating manufacturer shall furnish to the
manufacturer who prepares the product in final form for sale, barter or
exchange, a copy of all records relating to the manufacturing
operations performed by such participating manufacturer insofar as they
concern the safety, purity and potency of the lots of the product
involved, * * *.'' Other requirements regarding divided manufacturing
are contained in 21 CFR 610.63, which requires that ``If two or more
establishments participate in the manufacture of a product, the name,
address, and license number of each must appear on the package label,
and on the label of the container if capable of bearing a full label.''
The agency is clarifying the reporting requirements in
Sec. 600.80(c)(1)(iii) by substituting the term ``licensed
manufacturer'' for the term ``manufacturer.'' The agency intends that
the manufacturer licensed to prepare the final product for commercial
distribution has the primary responsibility for reporting adverse
experiences to FDA. To prevent duplicate reports, language has been
added to Sec. 600.80(c)(1)(iii) in this final rule to clearly delineate
the responsibilities of the licensed manufacturer of the final product
and other persons whose names may appear on the product label.
E. Reporting Requirements Section 600.80(c)
1. Failure of Pharmacologic Action
One comment on proposed Sec. 600.80(c) requested that FDA not
require single patient adverse experience forms for each failure of
expected pharmacological action. The comment suggested that increased
frequency analyses should not be performed on spontaneous lack of
response reports because it is not possible for an appropriate baseline
to be constructed using either domestic or foreign spontaneous reports
in this setting.
FDA believes that the use of single patient adverse experience
reporting forms provides the agency with information that may be
helpful in assessing whether there is a need for further investigation
of the reported lack of response. The agency also believes that
increased frequency analyses and reports are useful to serve as an
indicator that an investigation is needed to explore the issue further.
2. Followup Reports to 15-day Alerts
Two comments regarding proposed Sec. 600.80(c)(1)(i) questioned the
need for a report that briefly describes the steps taken to seek
additional information about an adverse event and the reasons why such
information could not be obtained. The comments stated that the
proposed language placed an additional burden on licensed manufacturers
by requesting not only that they make every effort to obtain such
information but also that they write a report describing such efforts.
Under Sec. 600.80(c) licensed manufacturers will be required to
seek additional information and document the steps taken to comply with
the rule in a manner consistent with Sec. 314.80(c). The agency is not,
at this time, specifying the format for this documentation. The agency
must be able to verify the licensed manufacturer's efforts and advise
licensed manufacturers of additional steps that should be pursued to
retrieve the necessary information when appropriate. The proposed rule
stated that this report should not be submitted to the agency unless so
requested but should be maintained in the licensed manufacturer's
files. This requirement differs from Sec. 314.80(c)(1)(i). The agency
believes it would reduce the burden for manufacturers who produce both
biologics and drugs if Sec. 600.80(c)(1)(i) is consistent with
Sec. 314.80(c)(1)(i). Therefore, the sentence in proposed
Sec. 600.80(c)(1)(i), ``This report should be retained by the
manufacturer in its files but not submitted as a followup to FDA unless
so requested'' has been deleted. Further discussion of changing the
final disposition of these reports is included in the notice of
proposed rulemaking found elsewhere in this issue of the Federal
Register.
3. Increased Frequency Analysis
Two comments on proposed Sec. 600.80(c)(1)(ii) requested
information regarding the utility of increased frequency analysis.
These comments suggest that the analysis is not of the increased
frequency of adverse experiences but rather the analysis is of the
increased frequency of reports of adverse experiences. One comment
requested that the agency develop improved methods for determining
increased frequency that would account for fluctuations in reporting.
FDA agrees that increased frequency of adverse experience reports
does not necessarily correlate with an increase in adverse experiences.
Case reports are used to alert the agency about areas which may need
further investigation. FDA takes into account the fact that reporting
rates vary over time in postmarketing surveillance when analyzing the
reporting rate for an individual biologic. FDA does not assume that an
increase in incidence of adverse experiences will automatically trigger
an increase in reports of adverse experience. Nor does the agency
assume that an increase in the number of reports of adverse experiences
necessarily indicates an increase in incidence of adverse experiences.
The agency believes that an increase in reporting rates, when taken
into account with other relevant information, may indicate that an
epidemiologic investigation is needed to explore the situation further.
4. Periodic Reports
Three comments on proposed Sec. 600.80(c)(2) noted a discrepancy on
when the reporting period begins. One comment requested that the
interval for periodic reporting be extended to annually rather than
quarterly. One comment requested that the agency extend the time for
submitting periodic reports from 30 to 60 days after the end of the
reporting period.
FDA believes that the reports need to be submitted in a timely
manner because the public is continuing to be exposed to the products.
Accordingly, FDA is retaining the proposed time schedule for submitting
periodic reports in this final rule. In the notice of proposed
rulemaking published elsewhere in this issue of the Federal Register,
FDA is proposing to amend the regulations regarding when the reporting
period begins and to amend the schedule for submitting periodic
reports.
5. Schedule for Submitting Reports
Four comments on proposed Sec. 600.80(c)(2)(i) requested that the
agency limit reporting requirements (other than 15-day alerts) to the
first 3 or 10 years of marketing. These comments stated that the
initial postmarketing period would provide the most benefit and that
after an initial period these reports would offer little benefit and
would be a burden to the agency and the licensed manufacturer.
FDA believes that there is a need for licensed manufacturers to
continually monitor adverse experiences. The length of time a product
is marketed does not guarantee that it will not be implicated in latent
adverse experiences that were not recognized previously. Novel adverse
experiences can occur when a biological product is used concomitantly
with another drug or biological product. In addition, a product that
has been on the market for many years can be implicated in adverse
experiences that were either previously undetected or unknown in the
scientific community. For these reasons, this requirement for periodic
review and submission of reports of adverse experiences is necessary
for the public safety. However, the licensed manufacturer can request a
waiver under Sec. 600.90 in order to decrease or eliminate the periodic
reporting requirements for older products with a proven safety record.
Under Sec. 600.80(c)(2)(i) the agency may also require more
frequent reports for products if appropriate; for example, products
with special safety or efficacy concerns. Similarly the agency may
require less frequent reports or no reports for products with a history
of continual safety.
6. Effect of Significant Change in Manufacturing on Reporting
Requirements
One comment on proposed Sec. 600.80(c)(2)(i) expressed concern that
significant changes in the manufacturing process, as provided in the
Product License Application (PLA), may lead FDA to require that the
frequency of the periodic reports be maintained as quarterly reports.
The example given in the comment was for influenza virus vaccine. The
comments questioned whether this product would be considered a new
product annually due to its inherent strain changes.
Influenza vaccine is an example of a product for which more
frequent reports may be appropriate. The agency considers the influenza
vaccine to be a new product annually because variations in influenza
strains make it necessary to reformulate the influenza vaccine each
year.
In the past, there have been many reports of adverse experiences
associated with the influenza vaccine, including reports of Guillain-
Barre Syndrome and false positive test results for other viral markers.
In situations such as this, the agency may require more frequent
reporting which will help it assess the magnitude and accuracy of
reports of adverse experiences. In Sec. 600.80(c)(2)(i) FDA may upon
written notice extend or reestablish the requirement that a licensed
manufacturer submit quarterly reports, or require that the license
manufacturer submit reports under this section at different times than
those stated. Prompt reporting of these adverse experiences will make
it easier to either recall a problem lot or discredit a false rumor.
7. Requirement for Negative Periodic Reports
Two comments on proposed Sec. 600.80(c)(2) requested that the
agency clarify the discrepancy between the proposed rule and the draft
guideline regarding periodic reports for products that had no adverse
experiences reported. The proposed rule did not require periodic
reports for products that had no adverse experiences reported. The
guideline asked that a letter be sent stating that no adverse
experiences were reported. These comments also stated that the negative
report is an ``undue burden.''
The guideline has been changed to be consistent with the final rule
in not requiring negative reporting at this time. However, the agency
believes that the negative reports are appropriate for the agency to
determine that the licensed manufacturer is focusing attention on
whether there have been adverse experiences reported to FDA. Therefore,
requirements regarding submission of negative reports are included in
the notice of proposed rulemaking found elsewhere in this issue of the
Federal Register.
8. Tabular Line Listing in Periodic Reports
Three comments on proposed Sec. 600.80(c)(2)(ii)(C) regarding the
tabular listing of adverse experiences required in the periodic reports
stated that the requirements to list the patient's identification
number, age, sex, and adverse experience terms in the tabular listing
were viewed as unnecessary and excessive. Also noted were discrepancies
regarding the tabular listing requirements between the guideline and
the proposed rule.
The agency agrees that the age and sex are not necessary in the
tabular listing. However, the agency believes that the adverse
experience terms should be included in such a listing. The tabular line
listing is intended to provide a synopsis of individual case histories
previously submitted, to assist FDA in identifying potential issues and
individual case histories for further review. The agency is amending
Sec. 600.80(c)(2) to require only the licensed manufacturer's patient
identification number and adverse experience terms in the tabular
listing.
9. Submission of Labeling
Two comments on proposed Sec. 600.80(c)(2)(ii)(E) requested that
the agency not require licensed manufacturers to submit with periodic
reports a copy of the most current labeling, including container
labels, carton labels, package inserts, and other materials distributed
with the product. In addition, the comments stated that the current
labeling is reviewed by FDA before use and licensed manufacturers
should not be required to repeatedly submit this information with
periodic reports. One comment stated that the only labeling useful for
evaluating adverse experience reports is the package insert, unless the
product is sold over-the-counter, then submission of directions for
consumers on the container label may be justified.
The agency agrees with the comments and is amending
Sec. 600.80(c)(2)(ii)(C) of the final rule to require ``a history of
actions taken since the last report because of adverse experiences (for
example, labeling changes or studies initiated).'' This ensures that
the review of the adverse experiences is conducted in the context of
the latest information available.
10. Submission of Distribution Data
Ten comments related to various aspects of the requirements in
proposed Sec. 600.80(c)(2)(iv) for submission of distribution data for
licensed biological products. Two comments stated that the request for
foreign distribution data is a heavy burden. Three comments stated that
the requirement to report dose distribution data is difficult and
inappropriate for certain types of products and that this information
is not required in Sec. 314.80 for drugs. Two comments disagreed with a
statement in the preamble that the quantity of a product distributed
enables FDA to estimate more accurately the incidence of a product's
adverse effects. The comments reasoned that distribution data do not
determine how much product is actually used. One comment questioned
FDA's ability to keep the distribution information confidential. One
comment stated that the proposed schedule for distribution reports
places a hardship on manufacturers as it required quarterly reports for
new biological products, annual reports for biological products
licensed more than 3 years, and annual reports for drugs. Another
comment requested guidance on the preferred format for distribution
data. The agency agrees that foreign distribution data should not be
required for biological products. Although the agency agrees that
distribution data do not accurately estimate the incidence of a
product's adverse effects, it is information needed to help FDA
determine whether further study is needed. FDA, on its own initiative,
is amending the final rule to parallel the drug regulations format by
moving the requirements to submit distribution data to Sec. 600.81. The
agency has revised the schedule for submitting distribution reports in
Sec. 600.81 of the final rule. The reports will now be due on the
semiannual and annual anniversary of the licensing of the product.
Licensed manufacturers that believe that the requirements for
submission of distribution data are inappropriate for certain types of
products may request a waiver under Sec. 600.90, as discussed elsewhere
in this preamble. Until a waiver is granted the provisions specified in
the final rule are applicable.
F. Review of Scientific Literature
One comment on Sec. 600.80(d) requested that submission of reports
from scientific literature be limited to those articles where the
author believes the product is associated with the experience; i.e.,
``reasonable causation'' by the author should be used in determining
what adverse experiences from the literature need to be reported to
FDA.
The agency believes that reports of adverse experiences in the
literature where the author clearly states that the licensed
manufacturer's product is not the cause do not need to be reported.
Reports in the scientific literature where no conclusion is reached
regarding causality should be further investigated by the licensed
manufacturer and reported to FDA if the adverse experience is
associated or remains possibly associated with the licensed biological
product. The licensed manufacturer should document the information that
determines the cause to be other than product related and retain this
documentation.
G. Reporting Form FDA-1639
Five comments on proposed Sec. 600.80(f) concerned the use of Form
FDA-1639 for reporting adverse experiences. One comment stated that the
form is inappropriate for their biological products, one comment asked
that the form be updated, one comment requested that Form FDA-1639 be
retained for VAERS reporting as well as for adverse experience
reporting for drugs and biological products. Two comments questioned
whether an approved alternate form for reporting adverse experiences
for drugs must be resubmitted to CBER for approval. One comment
requested that the agency not allow implementation of an alternative
reporting form as it will cause a hardship in computerization of
adverse experience data across the biological and pharmaceutical
product lines. This comment requested that the same form (Form FDA-
1639) be used for all adverse experience reports regardless of the
nature of the product.
FDA has designed a new adverse experience reporting form (Form FDA-
3500A) which, with the exception of reporting adverse experiences
associated with vaccines, is ordinarily to be used to report under
Secs. 310.305, 312.32, 314.80, 600.80, and parts 803 and 807 regarding
drugs, biological products, and devices, respectively. The new form
will simplify and consolidate the reporting of adverse events and
product problems and will enhance agency-wide consistency in the
collection of postmarketing data. Any computer-generated forms will
have to be submitted to MEDWATCH, 5600 Fishers Lane, Rockville, MD
20852-9787, for approval to use in complying with this final rule. As
one comment suggested, alternative formats will make computerization of
adverse experience data across product lines difficult. Therefore, a
licensed manufacturer should submit adequate justification for an
alternative format.
Form FDA-3500A is referenced in Sec. 600.80(f) of the final rule.
The term ``form designated by FDA'' is used throughout the remainder of
the final rule to accommodate any future changes in the form itself.
For vaccines the designated form for reporting adverse experiences is
Form VAERS-1. The form for VAERS is discussed in a published report in
Morbidity and Mortality Weekly Report (see MMWR, 39:730-733, 1990).
H. Reporter Identification
One comment on proposed Sec. 600.80(h) requested that if the
reporter is the patient (or relative) that his or her name not be
listed on the adverse experience form.
The agency concurs with this request for adverse experience
reporting for licensed biological products other than vaccine-
associated experiences being reported in accordance with NCVIA. Under
NCVIA it would be appropriate to include the patient's name in the
report because copies of this report may be made available to the
vaccinee or legal representative of the vaccinee. For adverse
experience reporting of licensed biological products other than
vaccines being reported under NCVIA, the report should not include the
name of the patient, but should assign a unique code number to each
report. For adverse experience reporting of biological products,
patient identifiers are not releasable to the public under FDA's public
information regulations (21 CFR part 20). Section 600.80(h) is amended
to reflect that VAERS reports are subject to the CDC Privacy Act
System.
I. Unique Code Number
One comment concerning proposed Sec. 600.80(h) requested that the
agency increase the number of characters in the unique code number
assigned to each report from eight characters in length to nine
characters.
The agency encourages consistency by designating in the final rule
a number of characters to be used, to simplify preparing and processing
the reports. To allow some flexibility, note that Sec. 600.80(h) in the
final rule recommends but does not require use of a code number of
eight characters or less.
J. Recordkeeping
Two comments on proposed Sec. 600.80(i) related to the length of
time a licensed manufacturer is required to keep adverse experience
records. One comment requested clarification regarding whether form
letters sent by the licensed manufacturer to the adverse experience
reporter must be retained 10 years; another comment requested that the
recordkeeping be limited to 1 year past the involved product's
expiration date.
FDA believes that 10 years is a reasonable time to maintain such
records. This requirement corresponds with existing regulations for
drug products. If a form letter to the reporter is the documentation
that the licensed manufacturer sought additional information about an
adverse experience, then the form letter must be maintained in the file
for 10 years. Any letters which are part of the correspondence
regarding an adverse experience reporting must be maintained in the
file for 10 years.
K. Exemptions
FDA has determined that Sec. 600.80(l) should be amended to clarify
that licensed manufacturers of in vitro diagnostic products, including
assay systems for the detection of antibodies or antigens to
retroviruses, report adverse experiences under the device reporting
regulations. The best way to monitor product defects with these
licensed biological devices is for them to be reported under the
Medical Devices: Medical Device User Facility, Distributor, and
Manufacturer Reporting, Certification, and Registration Regulations
(see 56 FR 60024, November 26, 1991). To eliminate any confusion over
how to report product defects with these products, the final rule is
amended to state specifically that in vitro diagnostics, including
assays to detect antibodies or antigens to retroviruses (such as HIV-1
and HIV-2), are exempt from this rule but are subject to the device
reporting regulations.
IV. Analysis of Impacts
FDA has examined the impacts of the proposed rule under Executive
Order 12866 and the Regulatory Flexibility Act (Pub. L. 96-354).
Executive Order 12866 directs agencies to assess all costs and benefits
of available regulatory alternatives and, when regulation is necessary,
to select regulatory approaches that maximize net benefits (including
potential economic, environmental, public health and safety, and other
advantages; distributive impacts; and equity). The agency believes that
this final rule is consistent with the regulatory philosophy and
principles identified in the Executive Order. In addition, the final
rule is not a significant regulatory action as defined by the Executive
Order and so is not subject to review under the Executive Order.
The Regulatory Flexibility Act requires agencies to analyze
regulatory options that would minimize any significant impact of a rule
on small entities. The final rule codifies adverse experience reporting
for biological products currently being practiced by licensed
manufacturers on a voluntary basis. FDA believes that the information
collection resulting from postmarket surveillance required by this
final rule will be of benefit to the public health. FDA has prepared a
Threshold Assessment to estimate the cost to comply with the final rule
by the regulated industry. The estimation by FDA for the total annual
cost to industry is $3,937,164. The agency certifies that the final
rule will not have a significant economic impact on a substantial
number of small entities. Therefore, under the Regulatory Flexibility
Act, no further analysis is required.
V. Environmental Impact
The agency has determined under 21 CFR 25.24(a)(8) that this action
is of a type that does not individually or cumulatively have a
significant effect on the human environment. Therefore, neither an
environmental assessment nor an environmental impact statement is
required.
VI. Paperwork Reduction Act of 1980
Sections 600.80 and 600.81 of this final rule contain information
collection requirements which are subject to review by the Office of
Management and Budget (OMB) under the Paperwork Reduction Act of 1980.
The title, description, and respondent description of the information
collection are shown below with an estimate of the annual reporting and
recordkeeping burden. Included in the estimate is the time for
reviewing instructions, searching existing data sources, gathering and
maintaining the data needed, and completing and reviewing the
collection of information.
Title: Adverse Experience Reporting Requirements for Licensed
Biological Products.
Description: FDA is charged with the responsibility for determining
that a biological product meets the statutory standards for safety,
purity, and potency for initial and continued licensure. To carry out
this mandate, the agency needs to be informed whenever a manufacturer
of a licensed biological product receives or otherwise becomes aware of
information about adverse experiences associated with the use of its
product. Only if FDA is provided with such information will it be able
to evaluate the risk, if any, associated with a biological product and
take whatever action is necessary to reduce or eliminate the public's
exposure. FDA is taking this action to provide a mechanism under which
manufacturers would inform the agency, on a timely basis, of any
unanticipated safety problems with marketed biological products. This
action is similar to initiatives taken by FDA regarding new drugs and
medical devices.
Description of Respondents: Businesses or other for-profit and
small businesses or organizations.
As required by the Paperwork Reduction Act, FDA has submitted a
copy of this rule to OMB with a request that it approve these
information collection requirements.
Estimated Total Annual Reporting Burden
--------------------------------------------------------------------------------------------------------------------------------------------------------
Number of Respondents
Section Number of Respondents per Respondent Total Annual Responses Hours Per Response Total Hours
--------------------------------------------------------------------------------------------------------------------------------------------------------
600.81 63 175.12698 11,033 1.0 11,033
--------------------------------------------------------------------------------------------------------------------------------------------------------
Estimated Total Annual Recordkeeping Burden
----------------------------------------------------------------------------------------------------------------
Total Recordkeeping
Section No. of Recordkeepers Annual Hours Per Recordkeeper Hours
----------------------------------------------------------------------------------------------------------------
600.80(i) 63 0.5 31.5
----------------------------------------------------------------------------------------------------------------
This final rule also contains information collection requirements
contained in Sec. 600.80(c) that have been approved by OMB under OMB
No. 0910-0291 with a total of 11,033 hours. It is estimated that the
information requirements for this section under this final rule will
add 11,064.5 hours to the burden estimate.
List of Subjects in 21 CFR Part 600
Biologics, Reporting and recordkeeping requirements.
Therefore, under the Federal Food, Drug, and Cosmetic Act, the
Public Health Service Act, and under authority delegated to the
Commissioner of Food and Drugs, 21 CFR part 600 is amended as follows:
PART 600--BIOLOGICAL PRODUCTS: GENERAL
1. The authority citation for 21 CFR part 600 is revised to read as
follows:
Authority: Secs. 201, 501, 502, 503, 505, 510, 519, 701, 704 of
the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 351, 352,
353, 355, 360, 360i, 371, 374); secs. 215, 351, 352, 353, 361, 2125
of the Public Health Service Act (42 U.S.C. 216, 262, 263, 263a,
264, 300aa-25).
2. A new subpart D consisting of Secs. 600.80, 600.81, and 600.90
is added to read as follows:
Subpart D--Reporting of Adverse Experiences
Sec.
600.80 Postmarketing reporting of adverse experiences.
600.81 Distribution reports.
600.90 Waivers.
Subpart D--Reporting of Adverse Experiences
Sec. 600.80 Postmarketing reporting of adverse experiences.
(a) Definitions. The following definitions of terms apply to this
section:
Adverse experience means any adverse event associated with the use
of a biological product in humans, whether or not considered product
related, including the following: an adverse event occurring in the
course of the use of a biological product in professional practice; an
adverse event occurring from overdose of the product, whether
accidental or intentional; an adverse event occurring from abuse of the
product; an adverse event occurring from withdrawal of the product; and
any failure of expected pharmacological action.
Blood Component for this purpose has the same meaning as defined in
Sec. 606.3(c) of this chapter.
Increased frequency means an increase in the rate of occurrence of
a particular adverse biological product experience, e.g., an increased
number of reports of a particular adverse biological product experience
after appropriate adjustment for biological product exposure.
Serious means an adverse experience associated with the use of a
biological product that is fatal or life-threatening, is permanently
disabling, requires inpatient hospitalization, or is a congenital
anomaly, cancer, or overdose.
Unexpected means an adverse biological product experience that is
not listed in the current labeling for the product and includes an
event that may be symptomatically and pathophysiologically related to
an event listed in the labeling, but differs from the event because of
greater severity or specificity. For example, under this definition,
hepatic necrosis would be unexpected (by virtue of greater severity) if
the labeling only referred to elevated hepatic enzymes or hepatitis.
Similarly, cerebral thromboembolism and cerebral vasculitis would be
unexpected (by virtue of greater specificity) if the labeling only
listed cerebral vascular accidents.
(b) Review of adverse experiences. Any person having a product
license under Sec. 601.20 of this chapter shall promptly review all
adverse experience information pertaining to its product obtained or
otherwise received by the licensed manufacturer from any source,
foreign or domestic, including information derived from commercial
marketing experience, postmarketing clinical investigations,
postmarketing epidemiological/surveillance studies, reports in the
scientific literature, and unpublished scientific papers.
(c) Reporting requirements. The licensed manufacturer shall report
to FDA adverse experience information, as described in this section.
The licensed manufacturer shall submit two copies of each report
described in this section for nonvaccine biological products, to the
Center for Biologics Evaluation and Research (HFM-210), Food and Drug
Administration, 1401 Rockville Pike, suite 200 N., Rockville, MD 20852-
1448. Submit all vaccine adverse experience reports to: Vaccine Adverse
Event Reporting System (VAERS), P.O. Box 1100, Rockville, MD 20849-
1100. FDA may waive the requirement for the second copy in appropriate
instances.
(1) Fifteen-day Alert reports. (i) The licensed manufacturer shall
report each adverse experience that is both serious and unexpected,
regardless of source, as soon as possible but in any case within 15
working days of initial receipt of the information. These reports are
required to be submitted, for nonvaccine biological products, on a form
designated by FDA or a suitable format containing all of the data
elements in the FDA designated reporting form, and, for vaccines on a
VAERS form. The licensed manufacturer shall promptly investigate all
adverse experiences that are the subject of these 15-day Alert reports
and shall submit followup reports within 15 working days of receipt of
new information or as requested by FDA. If additional information is
not obtainable, a followup report may be required that describes
briefly the steps taken to seek additional information and the reasons
why it could not be obtained. These 15-day Alert reports and followups
to them are required to be submitted under separate cover and may not
be included, except for summary or tabular purposes, in a periodic
report.
(ii) The licensed manufacturer shall review periodically (at least
as often as the periodic reporting cycle) the frequency of reports of
adverse biological product experiences that are both serious and
expected and reports of therapeutic failure (lack of effect),
regardless of source, and report any significant increase in frequency
as soon as possible but in any case within 15 working days of
determining that a significant increase in frequency exists. Upon
written notice, FDA may require that licensed manufacturers review the
frequency of reports of serious, expected adverse biological product
experiences at intervals different than the periodic reporting cycle.
Reports of a significant increase in frequency are required to be
submitted in narrative form (including the time period on which the
increased frequency is based, the method of analysis, and the
interpretation of the results), rather than using the form designated
by FDA. Fifteen-day Alert reports based on increased frequency are
required to be submitted under separate cover and may not be included,
except for summary purposes, in a periodic report.
(iii) The requirements of paragraphs (c)(1)(i) and (c)(1)(ii) of
this section, concerning the submission of Fifteen-day Alert reports,
shall also apply to any person other than the licensed manufacturer of
the final product whose name appears on the label of a licensed
biological product as a manufacturer, packer, distributor, shared
manufacturer, joint manufacturer, or any other participant involved in
divided manufacturing. In order to avoid unnecessary duplication in the
initial and followup submission of reports to FDA, the obligations of a
manufacturer other than the licensed manufacturer, may be met by
submitting all reports to the licensed manufacturer of the final
product. If a manufacturer other than the licensed manufacturer elects
to submit reports to the licensed manufacturer rather than to FDA, it
shall submit each report to the licensed manufacturer within 3 working
days of its receipt, and the licensed manufacturer shall then comply
with the requirements of this section. Under this circumstance, the
manufacturer shall maintain a record of this action which shall
include:
(A) A copy of all adverse biological product experience reports
submitted to the licensed manufacturer,
(B) Date the report was received by the manufacturer,
(C) Date the report was submitted to the licensed manufacturer,
(D) Name and address of the licensed manufacturer.
(iv) Each report submitted under this paragraph shall bear
prominent identification as to its contents, i.e., ``15-day Alert
report'' or ``15-day Alert report--followup.''
(2) Periodic adverse experience reports. (i) The licensed
manufacturer shall report each adverse experience not reported under
paragraph (c)(1)(i) of this section at quarterly intervals, for 3 years
from the date of issuance of the product license, and then at annual
intervals. The licensed manufacturer shall submit each quarterly report
within 30 days of the close of the quarter (the first quarter beginning
on the date of issuance of the product license) and each annual report
within 60 days of the anniversary date of the issuance of the product
license. Upon written notice, FDA may extend or reestablish the
requirement that a licensed manufacturer submit quarterly reports, or
require that the licensed manufacturer submit reports under this
section at different times than those stated. Followup information to
adverse experiences submitted in a periodic report may be submitted in
the next periodic report.
(ii) Each periodic report shall contain:
(A) A narrative summary and analysis of the information in the
report and an analysis of the 15-day Alert reports submitted during the
reporting interval (all 15-day Alert reports being appropriately
referenced by the licensed manufacturer's patient identification
number, adverse reaction term(s), and date of submission to FDA);
(B) A form designated for Adverse Experience Reporting by FDA for
each adverse experience not reported under paragraph (c)(1)(i) of this
section (with an index consisting of a line listing of the licensed
manufacturer's patient identification number and adverse reaction
term(s)); and
(C) A history of actions taken since the last report because of
adverse experiences (for example, labeling changes or studies
initiated).
(iii) Periodic reporting, except for information regarding 15-day
Alert reports, does not apply to adverse experience information
obtained from postmarketing studies (whether or not conducted under an
investigational new drug application), from reports in the scientific
literature, and from foreign marketing experience.
(d) Scientific literature. (1) A 15-day Alert report based on
information from the scientific literature shall be accompanied by a
copy of the published article. The 15-day Alert reporting requirements
in paragraph (c)(1)(i) of this section (i.e., serious, unexpected
adverse experiences) apply only to reports found in scientific and
medical journals either as case reports or as the result of a formal
clinical trial. The 15-day Alert reporting requirements in paragraph
(c)(1)(ii) of this section (i.e., a significant increase in frequency
of a serious, expected adverse experience or of a therapeutic failure)
apply only to reports found in scientific and medical journals either
as the result of a formal clinical trial, or from epidemiologic studies
or analyses of experience in a monitored series of patients.
(2) As with all reports submitted under paragraph (c)(1)(i) of this
section, reports based on the scientific literature shall be submitted
on the reporting form designated by FDA or comparable format as
prescribed by paragraph (f) of this section. In cases where the
licensed manufacturer believes that preparing the form designated by
FDA constitutes an undue hardship, the licensed manufacturer may
arrange with the Division of Biostatistics and Epidemiology (HFM-210)
for an acceptable alternative reporting format.
(e) Postmarketing studies. (1) Licensed manufacturers are not
required to submit a 15-day Alert report under paragraph (c) of this
section for an adverse experience obtained from a postmarketing
clinical study (whether or not conducted under a biological
investigational new drug application) unless the licensed manufacturer
concludes that there is a reasonable possibility that the product
caused the adverse experience.
(2) The licensed manufacturer shall separate and clearly mark
reports of adverse experiences that occur during a postmarketing study
as being distinct from those experiences that are being reported
spontaneously to the licensed manufacturer.
(f) Reporting forms. (1) Except as provided in paragraphs
(c)(1)(ii), and (f)(3) of this section, the licensed manufacturer shall
complete the reporting form designated by FDA (FDA-3500A, or, for
vaccines, a VAERS form) for each report of an adverse experience.
(2) Each completed form should refer only to an individual patient
or single attached publication.
(3) Instead of using a designated reporting form, a licensed
manufacturer may use a computer-generated form or other alternative
format (e.g., a computer-generated tape or tabular listing) provided
that:
(i) The content of the alternative format is equivalent in all
elements of information to those specified in the form designated by
FDA; and
(ii) the format is approved in advance by MEDWATCH: The FDA Medical
Products Reporting Program; or, for alternatives to the VAERS Form, by
the Division of Biostatistics and Epidemiology.
(4) Copies of the reporting form designated by FDA (FDA-3500A) for
nonvaccine biological products may be obtained from the Center for
Biologics Evaluation and Research (address above). Additional supplies
of the form may be obtained from the Consolidated Forms and
Publications Distribution Center, 3222 Hubbard Rd., Landover, MD 20785.
Supplies of the VAERS form may be obtained from VAERS by calling 1-800-
822-7967.
(g) Multiple reports. A licensed manufacturer should not include
in reports under this section any adverse experiences that occurred in
clinical trials if they were previously submitted in the product
license application. If a report refers to more than one biological
product marketed by a licensed manufacturer, the licensed manufacturer
should submit the report to the license for the product listed first in
the report.
(h) Patient privacy. For nonvaccine biological products, a
licensed manufacturer should not include in reports under this section
the names and addresses of individual patients; instead, the licensed
manufacturer should assign a unique code number to each report,
preferably not more than eight characters in length. The licensed
manufacturer should include the name of the reporter from whom the
information was received. The names of patients, health care
professionals, hospitals, and geographical identifiers in adverse
experience reports are not releasable to the public under FDA's public
information regulations in part 20 this of chapter. For vaccine adverse
experience reports, these data will become part of the CDC Privacy Act
System 09-20-0136, ``Epidemiologic Studies and Surveillance of Disease
Problems.'' Information identifying the person who received the vaccine
or that person's legal representative will not be made available to the
public, but may be available to the vaccinee or legal representative.
(i) Recordkeeping. The licensed manufacturer shall maintain for a
period of 10 years records of all adverse experiences known to the
licensed manufacturer, including raw data and any correspondence
relating to the adverse experiences.
(j) Guideline. FDA has prepared a guideline for the submission of
reports of adverse experiences and suggested followup investigation of
reports.
(k) Revocation of license. If a licensed manufacturer fails to
establish and maintain records and make reports required under this
section with respect to a licensed biological product, FDA may revoke
the product license for such a product in accordance with the
procedures of Sec. 601.5 of this chapter.
(l) Exemptions. Manufacturers of the following listed products are
not required to submit adverse experience reports under this section:
(1) Whole blood or components of whole blood.
(2) In vitro diagnostic products, including assay systems for the
detection of antibodies or antigens to retroviruses. These products are
subject to the reporting requirements for devices.
(m) Disclaimer. A report or information submitted by a licensed
manufacturer under this section (and any release by FDA of that report
or information) does not necessarily reflect a conclusion by the
licensed manufacturer or FDA that the report or information constitutes
an admission that the biological product caused or contributed to an
adverse effect. A licensed manufacturer need not admit, and may deny,
that the report or information submitted under this section constitutes
an admission that the biological product caused or contributed to an
adverse effect. For purposes of this provision, this paragraph also
includes any person reporting under paragraph (c)(1)(iii) of this
section.
Sec. 600.81 Distribution reports.
The licensed manufacturer shall submit information about the
quantity of the product distributed under the product license,
including the quantity distributed to distributors. The interval
between distribution reports shall be 6 months. Upon written notice,
FDA may require that the licensed manufacturer submit distribution
reports under this section at times other than every 6 months. The
distribution report shall consist of the bulk lot number (from which
the final container was filled), the fill lot numbers for the total
number of dosage units of each strength or potency distributed (e.g.,
fifty thousand per 10-milliliter vials), the label lot number (if
different from fill lot number), labeled date of expiration, number of
doses in fill lot/label lot, date of release of fill lot/label lot for
distribution at that time. If any significant amount of a fill lot/
label lot is returned, include this information. Disclosure of
financial or pricing data is not required. As needed, FDA may require
submission of more detailed product distribution information. Upon
written notice, FDA may require that the licensed manufacturer submit
reports under this section at times other than those stated. Requests
by a licensed manufacturer to submit reports at times other than those
stated should be made as a request for a waiver under Sec. 600.90.
Sec. 600.90 Waivers.
(a) A licensed manufacturer may ask the Food and Drug
Administration to waive under this section any requirement that applies
to the licensed manufacturer under Secs. 600.80 and 600.81. A waiver
request under this section is required to be submitted with supporting
documentation. The waiver request is required to contain one of the
following:
(1) An explanation why the licensed manufacturer's compliance with
the requirement is unnecessary or cannot be achieved,
(2) A description of an alternative submission that satisfies the
purpose of the requirement, or
(3) Other information justifying a waiver.
(b) FDA may grant a waiver if it finds one of the following:
(1) The licensed manufacturer's compliance with the requirement is
unnecessary or cannot be achieved,
(2) The licensed manufacturer's alternative submission satisfies
the requirement, or
(3) The licensed manufacturer's submission otherwise justifies a
waiver.
Dated: October 13, 1994.
William K. Hubbard,
Interim Deputy Commissioner for Policy.
[FR Doc. 94-26482 Filed 10-26-94; 8:45 am]
BILLING CODE 4160-01-F